This study is directly relevant to the National Institute of General Medical Sciences Division of Genetics and Developmental Biology's goal to support basic research in to the genetics of complex traits. One of the next great hurdles in the quest to improve human health is to understand complex disease traits that involve both genetic predisposition and environmental factors. In this study, I will develop Drosophila as a model system for the high throughput study of complex metabolic disease resulting from interactions between genotype and environment. Metabolic Syndrome, a constellation of energy metabolism-linked symptoms in humans, which has a prevalence of as much as 34% in developed countries, correlates with a dramatic increase in the risk of cardiovascular disease and type 2 diabetes. Metabolic Syndrome is a result of the environment (diet and activity levels) interacting with genotype. The immediate goals of this project are to test for the relative contributions of the "common disease-common variant" (CD-CV) and "rare allele of major effect" (RAME) hypotheses as the underlying genetic models and to parse the roles of different dietary components in the manifestation of Metabolic Syndrome-like symptoms in Drosophila. The specific aims are to 1: Screen for natural variation in phenotypic response to dietary manipulation (control, high sugar, high fat) and identify lines with aberrant metabolic responses to diet (e.g. excessive weight gain). 2: Identify genetic lines bearing major effect alleles for aberrant dietary response by testing for Mendelian inheritance;the frequency of major effect loci will elucidate whether the metabolic disorders are due to RAME or CD-CV. 3: Perform metabolomic profiles of over 200 metabolites and energy storage molecules in natural isolates showing varied response to diet to identify the metabolic pathways that may be responsible for the variations in response to diet. 4: Perform gene expression profiling to test for the correlation between enzyme expression and metabolite abundance in extreme dietary response phenotypes. Understanding the mechanisms underlying complex genetic disease requires manipulative experimentation, but humans are not good subjects for such experimentation. Model organisms such as Drosophila can be surveyed for natural genetic variation and then be subject to subsequent experimentation to identify the mechanisms of the complex genetic disease. Understanding the role of diet in exposing genetically based metabolic disorders hidden in a population (such as Metabolic Syndrome) is critical to learning how to treat and prevent metabolic disease in humans;Drosophila provides an ideal system to conduct these initial studies, necessary to develop testable hypotheses about the causes of the analogous human disease.